The applicant has been the recipient of an RSDA levels I and II from 1985 through 1995. During this period he has trained and conducted studies in the psychobiology and psychopharmacology of schizophrenia. This application is for a five year renewal of the RSDA level II award to enable the applicant to extend his work in the psychobiology of schizophrenia and acquire additional expertise in functional neuroimaging and neurobiology. In the last five years the applicant has successfully carried out a Prospective Study of Psychobiology in First Episode Schizophrenia that has characterized the clinical and biological course of the early stages of the illness and identified measures of prognosis and illness subtypes. These results have been widely presented and published in the scientific literature. He has also conducted a series of pilot studies addressing specific findings of the core project including the demonstration of antipsychotic drug effects on striatal morphology; and brain structure function relationships using event related potentials and MRI. In the next funding period the applicant plans to extend these lines of investigation by conducting a series of six projects. These include D.1) Prospective study of psychobiology and atypical antipsychotic treatment outcome in first episode schizophrenia- ascertainment of a new cohort; D.2) Prospective study of psychobiology in schizophrenia - long-term follow-up of the original cohort; D.3) The acute and long-term efficacy of clozapine in drug naive first episode schizophrenia in China; a randomized double-- blind comparison to chlorpromazine; D.4) In-vivo PET study of presynaptic and extracellular dopamine in drug naive first episode schizophrenia; D.5) Sensitization mechanisms in the pathophysiology of schizophrenia; D.60 Antipsychotic drug effects on basal ganglia morphology. The overarching hypothesis of this work is that the pathophysiology of schizophrenia involves a neurodegenerative process which can be characterized and treatment of which will prevent the deterioration and chronic morbidity of the illness.